DEGENERATION OF LOCUS COERULEUS NEURONS

蓝斑(LC)是世界上最大的去甲肾上腺素(NA)细胞群 中枢神经系统。在人类的LC中，有广泛的细胞丢失 年龄正常的人。LC神经元的过早丢失尤其显著 帕金森病、S病和阿尔茨海默病。其作用机制 LC背后的神经元死亡尚不清楚。我们最近发现， 大鼠一次全身注射NA神经毒素DSP-4可引起 LC轴突中去甲肾上腺素(NE)的迅速而严重的耗竭。这 神经递质耗竭后伴随着LC轴突的退化 在两周内，由于LC 6和LC 6中超过50%的细胞损失 给药12个月后。NA轴突的再生发生在 以前被DSP-4耗尽的前脑区，但脑干中没有 区域、小脑和脊髓。此应用程序的目标是 DSP4诱导的去甲肾上腺素、去甲肾上腺素耗竭关系的研究 轴突变性和NA神经元丢失，并探讨其机制 DSP-4诱导LC神经元死亡。 我们提出了三组实验：(1)描述起病和 NA神经元丢失的进展，我们将计算所有NA亚组的细胞 在DSP-4治疗后1至18个月。用于NA的鉴定 神经元我们将使用多巴胺-B-羟基酶变性，NA轴突 再生和LC神经元丢失，我们将把特定的子集标记为 额叶皮质、丘脑、小脑或脊髓。两周后， 大鼠将注射DSP-4或生理盐水，并将命运 逆行标记的NA神经元将在6个月后通过 研究DSP-4诱导的NE耗竭与LC之间的紧密联系 轴突变性，我们认为NE本身和自由基是在 去甲肾上腺素的氧化脱氨作用在DSP-4的神经毒性中起作用。我们 将通过确定NA的比率和程度来检验这一假设 影响DSP-4后轴突变性和NA神经元丢失的因素 用改变细胞内去甲肾上腺素水平的药物和药物进行预处理 这会降低中枢神经系统中谷胱甘肽的水平。

The locus coeruleus (LC) is the largest noradrenergic (NA) cell group in the central nervous system. In the human LC, there is extensive cell loss with normal aging. Premature loss of LC neurons is particularly dramatic in Parkinson;s disease and in Alzheimer's disease. The mechanisms underlying the LC neuron death are not known. We have recently found that a single systemic injection of the NA neurotoxin DSP-4 into rats causes rapid and profound depletion of norepinephrine (NE) from LC axons. This depletion of neurotransmitter is followed by degeneration of LC axons within two weeks and by loss of more than 50% of the cells in the LC 6 and 12 months after DSP-4 administration. Regeneration of NA axons occurs in forebrain regions previously depleted by DSP-4 but not in brainstem regions, cerebellum and spinal cord. The goals of this application are to characterize the relationship between the DSP-4 induced depletion of NE, NA axon degeneration and NA neuron loss, and to explore the mechanisms that underlie DSP-4 induced LC neuron death. We propose three sets of experiments: (1) To describe the onset and progression of NA neuron loss, we will count cells in all NA subgroups between 1 and 18 months after DSP-4 treatment. For identification of NA neurons we will use dopamine-B-hydroxylase degeneration, NA axon regeneration and LC neuron loss, we will label specific subsets into either frontal cortex, thalamus, cerebellum or spinal cord. Two weeks thereafter, rats will be injected with either DSP-4 or saline and the fate of retrogradely labeled NA neurons will be determined 6 months later by examining a tight linkage between the DSP-4 induced NE depletion and LC axon degeneration, we propose that NE itself and radicals formed during oxidative deamination of NE play role in the neurotoxicity of DSP-4. We will test this hypothesis by determining whether the rate and extent of NA axon degeneration and NA neuron loss after DSP-4 can be influenced by pretreatment with drugs that alter intracellular levels of NE and by drugs that reduce the levels of glutathione in the central nervous system.